The opioid receptor endorphin system consists of saturable, enantioselective, high affinity mu, delta and kappa opioid receptor types located in anatomically well defined areas of the mammalian CNS. Numerous endogenous opioid peptides (endorphins) function as the endogenous ligands for these receptors. This system mediates the analgesic, euphoric and addictive effects of narcotic drugs and contributes to regulation of numerous physiologic and behavioral functions in its normal state. This system is dysregulated by the abuse of prescription opioids, heroin, and other drugs. The abuse of prescription narcotic drugs alone in the U.S. is presently an enormous and growing problem. In 2010, about 360,000 emergency room episodes (nearly 1000/day) resulted from the abuse of prescription opioids, an increase of 79% from 2006. Landmark biophysical advances this year have resulted in the crystallization and X-ray structural determination of the mu, delta and kappa opioid receptors. These are enormously important results that will enable a much more precise understanding of how different classes of opioid drugs interact with the receptors to elicit their effects, both desirable and undesirable. In addition, recent pharmacologic advances have that highly selective delta receptor antagonists might be valuable medications for the treatment and prevention of human narcotic abuse that a drug showing a mu agonist-delta antagonist profile might produce strong analgesia without producing tolerance and dependence thus allowing continuous treatment of chronic pain. Optimal exploitation of these and other similarly intriguing observations now requires novel, exquisitely selective, nonpeptide ligands as research tools and potential medications. These new tools will enable the study of many questions of fundamental importance concerning the function of mu, delta and kappa opioid receptor subtypes and how drugs interact with their receptors to elicit these functions. We have continued to design, synthesize and evaluate novel drugs for this purpose during the reporting period. We earlier identified a mu agonist-delta antagonist and a delta inverse agonist in the 5-phenylmorphans series, a particularly interesting class of opioid receptor agonists that were originated by Everette May at NIH in 1955. We recently identified a morphine-like mu agonist and also a mu antagonist in a series of conformationally restrained 5-phenylmorphans. The diverse profiles obtained in this series illustrate the importance of subtle changes on the carbon-nitrogen skeleton and careful attention to stereochemical detail and provide important leads toward novel pain medications with reduced side effects and further understanding of drug-receptor interactions. Collaborative computer assisted molecular modeling and ab initio quantum mechanical methods are being employed in the design of these compounds. We have now developed a diastereoselective one-pot synthesis of 7- and 8-substituted 5-phenylmorphans and have utilized it to develop novel, high affinity opioid ligands. These and other novel drugs prepared in our studies are being (or will be) studied in the appropriate in vitro binding assays in native and cloned systems, smooth muscle assays, and in vivo assays in studies aimed at gaining further insight into the function of the opioid receptor endorphin system. Finally, We reviewed the mechanisms of central immune signaling and their implications for opioid analgesia.